生物谷報道：生活在大城市里的人與世世代代生活在封閉區(qū)域的人相比，其聰明程度的差距可能正在拉大,。美國華人科學(xué)家，芝加哥大學(xué)助教Bruce T. Lahn（中文譯為藍田）吃驚地發(fā)現(xiàn)：人類大腦中的一組“人性基因Humanness”仍在以超乎尋常的速度進化,！這一組基因決定前人類的腦容量以及智力的進化和發(fā)育,。由于這組基因的進化與人所處的社會的文明活動有關(guān)，大腦的加速進化還可能帶來一些社會后果———可能會導(dǎo)致不同社會中的人種間的智力發(fā)展不平衡,。這一組基因是通過對大量的高等生物的基因組比較篩選出的候選基因,。
The foreground shows brain images of human, macaque monkey, rat, and mouse (from top to bottom), as well as the phylogenetic relationship among these four taxa. The background shows DNA sequences. Brain complexity has increased dramatically in primates relative to rodents, and the increase is particularly pronounced in the lineage leading to humans. At the molecular level, genes involved in nervous system function also show accelerated rates of evolution in primates, especially in the lineage leading to humans. Thus, the dramatic phenotypic evolution of the brain in the origin of Homo sapiens is correlated with salient molecular evolution.
Cover image, Cell, December 29, 2004; illustrator, Sean Gould. See also Dorus, S., Vallender, E.J., Evans, P.D., Anderson, J.R., Gilbert, S.L., Mahowald, M., Wyckoff, G.J., Malcom, C.M., and Lahn, B.T. 2004. Cell 119:1027–1040.
這一研究結(jié)果刊登在今日美國出版的Science雜志上,，由華裔科學(xué)家藍田領(lǐng)導(dǎo)的研究小組的新發(fā)現(xiàn)有可能引發(fā)人類學(xué)家激烈的爭論,。藍田同一課題的兩篇論文同時發(fā)表在一期Science雜志上，實屬罕見,，這兩篇論文分別介紹了人腦中兩個正在高速進化的“人性基因Humanness”,，以證明人類大腦仍在高速進化。其中一個名為ASPM的基因在距今5800年前才出現(xiàn),；另一個名為Mi-crocephalin的基因是距今37000年前出現(xiàn)的,。此前，人類學(xué)家認為20萬年前現(xiàn)代人出現(xiàn)之后,，人類進化就“定型”了,，藍田等人的研究可能引起人類學(xué)家對現(xiàn)代人進化速度的重新關(guān)注?？茖W(xué)家認為,，這兩個“新基因”可能決定人腦的容量，進而可能影響到人類的智力水平,。為此Science同一期還發(fā)表了兩篇述評,，見附文。
據(jù)藍田的博士后項鵬介紹,，從1998年開始,，藍田通過對全基因組范圍內(nèi)與神經(jīng)系統(tǒng)有關(guān)的兩百多個基因的系統(tǒng)性研究,，并對人類、猴子,、大鼠和小鼠進行比較,，發(fā)現(xiàn)靈長類（人、猴）的神經(jīng)系統(tǒng)基因的進化速度比嚙齒類（老鼠等）高出30%,；而在靈長類中,，神經(jīng)系統(tǒng)基因的進化速度尤其迅速。2004年同樣一篇階段性成果發(fā)表在Cell上,。
科學(xué)家推測,，這兩個“新基因”的出現(xiàn)可能與農(nóng)耕,、語言,、文字等人類文明活動的出現(xiàn)有關(guān)，這似乎表明了人類基因進化隨著社會文明的不斷發(fā)展而推進,，兩者之間存在一種因果關(guān)系,。另一方面，由于人類文明發(fā)展速度不平衡,，一些落后地區(qū)的人大腦中“人性基因”的進化速度可能較為緩慢,。
美國科學(xué)家８日說，基因分析表明,，直到現(xiàn)在為止人類的大腦一直在快速進化過程中,，而且這種進化與人類文明的興起有密切聯(lián)系。
早先的化石和基因證據(jù)表明,，人類和黑猩猩在約６００萬年前由共同的祖先“分家”,，此后人類祖先的大腦快速進化，并產(chǎn)生了較高級的認知功能,，直至距今約２０萬年前現(xiàn)代智人出現(xiàn)為止,。在人們的習(xí)慣觀念中，現(xiàn)代人類大腦在生理上已經(jīng)“定型”了,。
由芝加哥大學(xué)科學(xué)家藍田博士領(lǐng)導(dǎo)的一個研究小組,，對人類體內(nèi)管理腦容量大小的兩個基因的演變進行分析。他們共搜集了世界各地５９個民族,、１０００多人的基因樣本,，并發(fā)現(xiàn)這兩個基因都正在進化中，現(xiàn)代人的大腦沒有“定型”,。
藍田解釋說,，這種進化并不是同時發(fā)生在整個種群中，而是一個漫長的選擇過程,。極少數(shù)個體率先發(fā)生基因變異,，出現(xiàn)新的單模態(tài),，而基因的新單模態(tài)使這些個體獲得生存和繁衍的優(yōu)勢，然后在整個種群中傳播,。
研究人員發(fā)現(xiàn),，這兩種對大腦發(fā)育至關(guān)重要的基因在自然選擇的壓力下以超乎尋常的速度進化。７０％的現(xiàn)代人小腦癥基因的單模態(tài),，是距今３．７萬年前首次出現(xiàn)的,；而３０％現(xiàn)代人異常紡錘型小腦畸形癥相關(guān)基因的單模態(tài)，是在５８００年前首次出現(xiàn),。兩種形態(tài)的出現(xiàn)都大大晚于２０萬年前出現(xiàn)的現(xiàn)代人類,。
研究人員說，這些新近出現(xiàn)的基因變異,，在時間上與人類文明的興起有密切聯(lián)系,。人類歷史上首次出現(xiàn)復(fù)雜工具制造、藝術(shù),、音樂等是在５萬年前,，而人類最古老的文明——美索不達米亞文明在公元前７０００年興起。
他們猜測,，文明的出現(xiàn)使人類面臨的環(huán)境更加復(fù)雜,，也加快了選擇的過程，因此優(yōu)勢的基因單模態(tài)能很快傳播,。
藍田說,，人類大腦的容量和復(fù)雜度仍然在快速進化中，現(xiàn)代人類面臨的環(huán)境變化更快,，也需要更復(fù)雜的技能,，而人腦將繼續(xù)通過適應(yīng)性選擇來進化，跟上變化的環(huán)境,。生物谷專家認為藍田博士的研究使人類從分子水平對人類的進化作了新的闡述，是分子進化學(xué)的研究上的里程碑式的研究,，從分子角度揭示了高等生物,，尤其是人類進化之謎?！?/p>
本期Science上的兩篇藍田博士文章及兩篇評論
Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in Humans
Patrick D. Evans, Sandra L. Gilbert, Nitzan Mekel-Bobrov, Eric J. Vallender, Jeffrey R. Anderson, Leila M. Vaez-Azizi, Sarah A. Tishkoff, Richard R. Hudson, and Bruce T. Lahn
Science 9 September 2005: 1717-1720
[Abstract] [Full Text] [PDF] [Supporting Online Material]
Ongoing Adaptive Evolution of ASPM, a Brain Size Determinant in Homo sapiens
Nitzan Mekel-Bobrov, Sandra L. Gilbert, Patrick D. Evans, Eric J. Vallender, Jeffrey R. Anderson, Richard R. Hudson, Sarah A. Tishkoff, and Bruce T. Lahn
Science 9 September 2005: 1720-1722
[Abstract] [Full Text] [PDF] [Supporting Online Material]
Are Human Brains Still Evolving? Brain Genes Show Signs of Selection
Michael Balter
Science 9 September 2005: 1662-1663
[Summary] [Full Text] [PDF]
A Human-Specific Gene in Microglia
Toshiyuki Hayakawa, Takashi Angata, Amanda L. Lewis, Tarjei S. Mikkelsen, Nissi M. Varki, and Ajit Varki
Science 9 September 2005: 1693
[Abstract] [Full Text] [PDF] [Supporting Online Material]
國外報道：
Accelerated Evolution of Nervous System Genes in the Descent of Homo sapiens
Thus far, most efforts to study the genetic basis of human brain evolution have focused on one gene (or one gene family) at a time. The ad hoc nature of these studies (and their scarcity) made it difficult to discern broad evolutionary trends. To address whether the evolution of the human brain has left genome-wide genetic imprints, we systematically examined the evolutionary history of more than 200 genes implicated in diverse biological aspects of the human nervous system. Coding sequences of these genes were compared across four mammalian taxa—human, macaque (an Old World monkey), rat, and mouse. For each gene, the nonsynonymous-to-synonymous substitution ratio (Ka/Ks) was calculated separately for primates (based on human-macaque comparison) and for rodents (based on rat-mouse comparison). The Ka/Ks ratio is a measure of protein evolution rate as scaled to neutral mutation rate.
Our analysis showed that, on average, Ka/Ks for nervous system genes is higher in primate than in rodent (by more than 30 percent), indicating that the proteins encoded by these genes have evolved about 30 percent faster in primates. Moreover, when examining only the subset of genes that function predominantly in nervous system development, the primate-rodent disparity in Ka/Ks became even more pronounced (more than 50 percent higher in primates than rodents). By contrast, genes that function primarily in the routine physiology and maintenance of the nervous system showed much less primate-rodent disparity. Within primates, the increase in Ka/Ks is most pronounced in the lineage leading from ancestral primates to humans. These observations argue that the remarkable phenotypic evolution of the human nervous system is correlated with accelerated evolution in the protein-coding regions of the underlying genes, particularly those genes involved in the development of the nervous system. The above trends are the result of a large number of mutations scattered across many nervous system genes.
Our study shed light on several long-standing questions regarding the genetic basis of human brain evolution. The first is whether functionally important mutations have occurred predominantly in protein-coding regions or regulatory regions of genes. Our data suggest that changes in coding regions are likely to be important, although this conclusion does not in any way imply that regulatory changes are necessarily less important to brain evolution. The study also asked whether many genes or just a few key genes confer the increase in brain size and structural complexity. The results suggest that a large number of mutations in many genes are probably needed to produce the dramatic structural changes observed in the human brain. Indeed, it can be roughly estimated that there is, on average, an excess of 1–2 nonsynonymous substitutions in primates over rodents for every nervous system gene. When only the developmental subgroup of genes is considered, the excess rises to 3–4 nonsynonymous substitutions per gene in primates over rodents. Thus, thousands of mutations in many hundreds (or possibly even thousands) of genes might have contributed to the evolution of the human brain. The third question addressed by the study is how easily detectable these functionally important mutations are. The results suggest that the human genome (when analyzed in conjunction with the genomes of other species) might contain an abundance of “smoking guns” that are informative about the genetic changes important for the emergence of the human form.
To extend our analysis to the entire genome, we are taking advantage of the growing number of mammalian genomes that have been sequenced. These studies should not only offer additional broad insights but also provide an entry point for identifying individual genes that have played important roles in human evolution.
Candidate “Humanness” Genes
Although they shed broad light on how the human brain evolved at the genetic level, the evolutionary trends described above do not immediately reveal the specific genes (or mutations) that are key to human brain evolution. The second major objective of our research is to use a multistep strategy to identify such genes.
In the first step, we perform large-scale comparisons of genes across multiple species in a manner similar to the comparative study described above. This allows us to identify “outliers” in the genome—i.e., genes exhibiting a rate of evolutionary changes in the human lineage that is significantly greater than that of the other mammalian lineages. In the second step, we compare outlier genes over a much wider range of primate and nonprimate taxa, to confirm the exceptional nature of their accelerated evolution in the human lineage. In the third step, we subject genes with the most interesting evolutionary patterns to polymorphism studies in humans. Through combined analysis of polymorphism data and divergence data—for example, by using the McDonald-Kreitman test—we can discern whether the accelerated evolution in the human lineage is due to positive selection.
Employing the above strategy, we identified a number of candidate genes that might have played a role in the evolution of the human brain (candidate “humanness” genes). In humans, homozygous loss-of-function mutations in two of these genes, ASPM or Microcephalin, cause microcephaly, a congenital developmental defect characterized by severely reduced brain size. Although their brains are smaller, affected subjects have relatively normal brain structure and no overt abnormalities outside of the nervous system. Based on these observations, it was concluded that ASPM and Microcephalin are specific regulators of brain size. The two genes share a similar set of evolutionary properties. First, they show significantly accelerated evolution in primates relative to nonprimate mammals. Second, within primates, this acceleration is most prominent in the lineage leading to humans. Third, comparison of interspecies divergence data with human polymorphism data confirmed that the accelerated evolution in the human lineage is likely due to positive selection. Finally, the accelerated evolution appears to be highly localized within specific regions of these genes, suggesting that positive selection has targeted certain domains of the genes more intensely than others. The above data provide compelling evidence that ASPM and Microcephalin have been the target of strong positive selection during primate evolution, and such selection is most prominent in the human lineage.
Is the Human Brain Still Evolving?
The most salient trend in the evolutionary history of Homo sapiens is the rapid increase of brain size and complexity. Could this trend be continuing even in modern-day humans? To address this question, we focused on the set of candidate “humanness” genes we found through comparative genomics analysis and searched for evidence of ongoing adaptive evolution among present-day humans. We reasoned that if a gene has evolved adaptively in the making of the human species, it may well continue to undergo adaptive evolution even after the emergence of anatomically modern humans. Based on the analysis of human polymorphism patterns, we found evidence that some of these genes are experiencing ongoing positive selection in modern humans, suggesting that the human brain is still evolving actively toward new and more adaptive forms.
Other Research Activities
Within the evolution field, we are also interested in identifying genome-wide patterns. For example, our recent study showed that a strong correlation exists between the fixation probability of nonsynonymous mutations and mutation rate. This highly unexpected finding indicates that the probability by which new mutations are accepted during evolution is affected not only by selection—as postulated by the long-standing theoretical paradigm—but also by mutation rate. The fact that our finding cannot be reconciled with prevailing theories suggests that the current theoretical framework of molecular evolution may need a major revision.
Another research emphasis of my lab is stem cell biology, which includes two broad aims. First, we attempt to understand the molecular mechanisms that render pluripotency to stem cells, or conversely, restricted cellular phenotype to differentiated cells. We are testing the hypothesis that the restriction of cell fate during development is achieved, at least in part, by secluding key regulatory genes from the cell's transcriptional machinery. The second aim of our stem cell research is to explore applications of these cells in therapy. We are using both in vitro and in vivo approaches to develop methods to differentiate stem cells into desired cell types. We are also testing the therapeutic potential of stem cells in animal models. Some of our stem cell work, especially that aimed at therapeutic applications, is done in collaboration with the Center for Stem Cell Biology and Tissue Engineering at Sun Yat-sen University, China.
Finally, our lab is interested in neurogenetics. We recently cloned a mouse gene corresponding to a hypertonia phenotype (i.e., increased muscle tone). Further characterization of the gene showed that it plays a critical role in regulating the homeostasis of GABAA receptors in neurons, probably by modulating the endocytic recycling of GABAA receptors. In mutant mice, GABAA receptor concentration is dramatically reduced, leading to disinhibition of motor neurons (and hence hypertonia). In another project, which combines stem cell biology with neurogenetics, we knocked out a mouse gene that has been suggested by other people's work to play an important role in the development of neural stem cells. Knockout mice showed a severe developmental defect of the nervous system that is likely due to the misregulation of neural stem cells. In a related project, we are developing a set of genetic tools to study the function and fate of neural stem cells in the adult mouse brain.
Grants from the National Institutes of Health, the Burroughs Wellcome Fund, and the Searle Scholars Program provided support for these projects.
Bruce T. Lahn, Ph.D. 簡介及實驗室,，聯(lián)系方式
University of Chicago
Department of Human Genetics
Cummings Life Sciences Center
920 E. 58th St., 3rd Floor
Chicago, Illinois 60637
Phone: 773-834-4065
Fax: 773-834-8470
[email protected]
Bruce T. Lahn博士近年幾年的重要論文
Gilbert SL, Dobyns WB, Lahn BT.Genetic links between brain development and brain evolution.
Nat Rev Genet. 2005 Jul;6(7):581-90. Review.
Wyckoff GJ, Malcom CM, Vallender EJ, Lahn BT. A highly unexpected strong correlation between fixation probability of nonsynonymous mutations and mutation rate.
Trends Genet. 2005 Jul;21(7):381-5. Review
Vallender EJ, Pearson NM, Lahn BT. The X chromosome: not just her brother's keeper.
Nat Genet. 2005 Apr;37(4):343-
Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, Mahowald M, Wyckoff GJ, Malcom CM, Lahn BT.Accelerated evolution of nervous system genes in the origin of Homo sapiens.
Cell. 2004 Dec 29;119(7):1027-40.
Dorus S, Evans PD, Wyckoff GJ, Choi SS, Lahn BT. Rate of molecular evolution of the seminal protein gene SEMG2 correlates with levels of female promiscuity.
Nat Genet. 2004 Dec;36(12):1326-9
